Head Direction (HD) cells encode the horizontal direction that the head is pointing in an environment. These cells display experience-dependent modification but the mechanism for this plasticity has not yet been discovered. As an example, if an animal is manually moved from a familiar to a novel environment, the preferred direction of an HD cell will usually be different in the two environments. In contrast, if an animal walks from the old environment to the new environment, the preferred direction in the new environment will be similar to that of the old environment, and this preferred direction will be maintained on future exposures even if the animal is manually placed in that environment. These findings indicate that a lasting environment-specific directional representation is formed within the HD network during the initial exposure to an environment. The long term goal of this work is to better characterize how the HD system can change as a result of experience and to determine the physiological mechanisms of this plasticity. The objective of this application is to formalize a set of procedures to investigate this form of experience-dependent plasticity and to investigate the cellular mechanism of this neural change by determining if it is dependent on the functioning of the NMDA subtype of the glutamate receptor, a neurotransmitter receptor that has been shown to be important for spatial memory. The central hypothesis is that the signal carried within the HD network shows modification as a result of experience and that this characteristic can be investigated in ways similar to that used to investigate other forms of learning. Guided by strong preliminary data, the following three specific aims will be accomplished: 1) Develop testing procedures that reliably demonstrate how the directional signal carried within the HD system can change based on landmark and self-movement cues encountered during initial exposure to an environment;2) Determine if the ability of landmarks to acquire control of the HD system is dependent on NMDA receptor-mediated transmission. This will be accomplished by administering a drug that blocks NMDA transmission when the animal is first exposed to a novel environment to see if NMDA blockade prevents long- lasting modification of the HD network;and 3) Determine if the ability of self-movement cues to maintain a stable and long-lasting directional signal in a new environment is dependent on NMDA receptor-mediated transmission. This will be accomplished by administering NMDA blockade during a procedure in which the HD system normally uses self-movement cues to maintain and establish an environmental-specific directional representation. The proposed work is innovative because it will link the areas of navigation, physiology of learning, and cellular models of navigation in novel ways. The proposed work is significant to human health because it will advance our understanding of plasticity in the circuitry allowing an organism to accurately orient in a new environment and will further our understanding of the impairment in this ability often seen as a result of neurological pathology such as stroke or Alzheimer's disease. PUBLIC HEALTH RELEVANCE: The proposed study represents a novel approach to understanding the nervous system processes that allow an individual to maintain spatial orientation when entering a new environment. These experiments are relevant to public health because they will provide new insight into the nature of spatial impairment that occurs in neurological disorders such as stroke or Alzheimer's disease.